Adiponectin (ADP) is an adipocyte hormone involved in glucose and lipid metabolism. We detected a rise in ADP in cerebrospinal fluid after intravenous (i.v.) injection, consistent with brain transport. In contrast to leptin, intracerebroventricular (i.c.v.) administration of ADP decreased body weight mainly by stimulating energy expenditure. Full-length ADP, mutant ADP with Cys39 replaced with serine, and globular ADP were effective, whereas the collagenous tail fragment was not. Lep(ob/ob) mice were especially sensitive to i.c.v. and systemic ADP, which resulted in increased thermogenesis, weight loss and reduction in serum glucose and lipid levels. ADP also potentiated the effect of leptin on thermogenesis and lipid levels. While both hormones increased expression of hypothalamic corticotropin-releasing hormone (CRH), ADP had no substantial effect on other neuropeptide targets of leptin. In addition, ADP induced distinct Fos immunoreactivity. Agouti (A(y)/a) mice did not respond to ADP or leptin, indicating the melanocortin pathway may be a common target. These results show that ADP has unique central effects on energy homeostasis.

The association between obesity and diabetes supports an endocrine role for the adipocyte in maintaining glucose homeostasis. Here we report that mice lacking the adipocyte hormone resistin exhibit low blood glucose levels after fasting, due to reduced hepatic glucose production. This is partly mediated by activation of adenosine monophosphate-activated protein kinase and decreased expression of gluconeogenic enzymes in the liver. The data thus support a physiological function for resistin in the maintenance of blood glucose during fasting. Remarkably, lack of resistin diminishes the increase in post-fast blood glucose normally associated with increased weight, suggesting a role for resistin in mediating hyperglycemia associated with obesity.

Resistin was originally reported as an adipose tissuespecific hormone that provided a link between obesity and diabetes. Resistin protein level was elevated in obese mice and decreased by insulin-sensitizing thiazolidinediones. Immunoneutralization of resistin improved insulin sensitivity in diet-induced obese mice, while the administration of exogenous resistin induced insulin resistance. More recently, we have shown that ablation of the resistin gene in mice decreased fasting glucose through impairment of gluconeogenesis, while resistin treatment in these knockout mice increased hepatic glucose production. However, the link between resistin and glucose homeostasis has been questioned by studies demonstrating reduced, rather than increased, resistin mRNA expression in obese and diabetic mice. To better understand the regulation of resistin, we developed a sensitive and specific RIA resistin that could accurately measure serum resistin levels in several mouse models. We show that while resistin mRNA is indeed suppressed in obese mice, the circulating resistin level is significantly elevated and positively correlated with insulin, glucose, and lipids. Both resistin mRNA expression and protein levels in Lep ob/ob mice are suppressed by leptin treatment in parallel with reductions in glucose and insulin. In wildtype mice, serum resistin increases after nocturnal feeding, concordant with rising levels of insulin. Resistin mRNA and protein levels decline in parallel with glucose and insulin during fasting and are restored after refeeding. We performed clamp studies to determine whether resistin is causally related to insulin and glucose. Adipose resistin expression and serum resistin increased in response to hyperinsulinemia and further in response to hyperglycemia. Taken together, these findings suggest that the nutritional regulation of resistin and changes in resistin gene expression and circulating levels in obesity are mediated, at least in part, through insulin and glucose.

It is well recognized that feeding behavior in mammals is orchestrated by neurons within the medial basal hypothalamus. However, it remains unclear whether food intake is also under the control of glial cells. Here, we combine chemical genetics, cell-type-specific electrophysiology, pharmacology, and feeding assays to show that stimulation of astrocytes within the medial basal hypothalamus reduces both basal- and ghrelin-evoked food intake. This occurs by a mechanism of adenosine-mediated inactivation of the orexigenic agouti-related peptide (AGRP) neurons in the hypothalamic arcuate nucleus (ARC) via adenosine A1 receptors. Our data suggest that glial cells participate in regulating food intake by modulating extracellular levels of adenosine. These findings reveal the existence of a glial relay circuit that controls feeding behavior, one that might serve as a target for therapeutic intervention in the treatment of appetite disorders.